It has been reported that novel natural products Lomaiviticins A and B, isolated from the actinomycete Micromonospora lomaivitiensis, are potent antitumor and antibiotic agents (He, H. et al., J. Am. Chem. Soc. 2001, 123, 5362-5363). These lomaiviticins are potent DNA cleaving agents with in vitro cytotoxicity against a number of cell lines with IC50 values ranging from 0.01 to 98 ng/mL. Inspection of the structures of the lomaiviticins leads to the recognition of the following structural elements: (a) the diazo groups; (b) the tetracyclic framework of the monomeric unit; (c) the carbohydrate moieties; (d) the hindered central carbon-carbon bond linking the two units; (e) the readily labile β-alkoxy functionality at C-3 and C-3′ and (f) the dicarbonyl core structure in lomaivitivin A.
On the other hand, patents revealed that benzoylacrylamide derivatives, containing dicarbony group, have intensive tyrosine kinase inhibiting activity and can be used as anticancer agents (U.S. Pat. Nos. 5,618,829; 4,130,661; EP Patent Application No. 0608897A2). It is well known that tyrosine kinase plays an important role in intercellular signal transduction and cell differentiation or growth. Accordingly, failure of control of tyrosine kinase activity in cells disorders intercellular signal transduction and causes abnormal cell differentiation/growth, which is considered to be directly responsible for the development of various diseases. In particular, it is known that tyrosine kinase is significantly associated with disorderly overgrowth of cancer cells. It has been proposed that an agent specifically inhibiting tyrosine kinase activity would be an anti-cancer agent having minor side-effects and exerting its therapeutic effect through novel mechanisms.
The recognitions of the dicarbonyl group in the novel natural product lomaiviticin A as one of the core structures to exert its anticancer activity, together with the novel tyrosine kinase inhibitory activity of benzoylacrylamide derivatives, lead inventors of the present invention to devote them to a study for developing a new class of dicarbonyl derivatives. Accordingly, the purpose of the present invention is to provide a family of novel compounds useful for suppressing the growth of cancer cells, which compounds are easily available, exhibit specific and intensive activity in inhibiting tyrosine kinase of the growth factor receptor, and show negligible side-effects compared with previously known anti-cancer agents.
Several reports have disclosed the preparation of some dicarbonyl derivatives. The synthesis of 1,4-diketones have been disclosed in the publication by (a) Rathke, M. W. et al (J. Am. Chem. Soc. 1971, 93, 4605-4606); (b) Dessau, R. M et al (J. Org. Chem. 1974, 39, 3457-3459); (c) Ito, Y. et al (J. Am. Chem. Soc. 1975, 97, 2912-2914); (d) Ito, Y. et al (J. Am. Chem. Soc. 1977, 99, 1487-1493); (e) Frazier, R. H et al (J. Org. Chem. 1980, 45, 5408-5411); (f) Paquette, L. A. et al (J. Org. Chem. 1995, 60, 7277-7283). For example, [4,4′-bycyclohexenyl]-3,3′-dione can be prepared from 2-cyclohexene-1-one, which was converted to its enolate with LDA and oxidized with ferric chloride (J. Org. Chem. 1980, 45, 5408-5411). Copper chloride and silver oxide have also been used as the oxidative reagents (J. Am. Chem. Soc. 1977, 99, 1487-1493; J. Am. Chem. Soc. 1975, 97, 649). The syntheses of benzoylacrylamide derivatives have been disclosed in patents (U.S. Pat. Nos. 5,618,829; 4,130,661; EP Patent Application No. 0608897A2). For example, 3,4-dimethoxyacetophenone reacted with glyoxylic acid monohydrate under reflux provided the corresponding substituted benzoylacrylic acid, which can be converted to various amides (U.S. Pat. No. 5,618,829). The synthesis of oxime, such as oxime derivatives of radicicol, was reported for their preparation (Ikuina, Y. et al, J. Med. Chem. 2003, 46, 2534-2541). The preparation of isoxazoles were also revealed (Hansen, T. V. et al, J. Org. Chem. 2005, 70, 7761-7764; PArHi, A. K. et al, Org. Lett. 2004, 6, 3063-3065; Himo, F. et al, J. Am. Chem. Soc. 2005, 127, 210-216; WO 2004/072051 A1).